Effects of diet on amyloid-β toxicity in the model organism C. elegans
Date
2018
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
University of Delaware
Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that currently affects over 5.5 million people in the United States and 40 million worldwide. AD is the leading cause of dementia, accounting for over 80% of cases, yet it is still poorly understood. The extracellular accumulation of the peptide amyloid-β (Aβ) results in senile plaques, a hallmark characteristic of AD. Recently, studies have shown that small, soluble oligomers approximately 40-46 peptides in length aggregate intracellularly and have a more toxic affect than the large, insoluble plaques. We are utilizing a transgenic strain of the model organism C. elegans that expresses toxic Aβ1-42 to identify factors which affect Aβ toxicity. Shifting Aβ animals to 25oC results in a severe, irreversible, time-dependent paralysis. C. elegans feed on E. coli in the laboratory setting and we found that the strain of E. coli consumed by Aβ animals significantly alters the onset of their paralysis. To determine mechanisms by which diet affects Aβ toxicity we took a candidate gene approach to evaluate the effects from loss-of-function mutations in genes known to alter Aβ toxicity. Specifically, loss of the prohibitin PHB-2, which is known to strongly induce the mitochondrial UPR (UPRmt), as well as loss of the thioredoxin reductase TRXR-2, which is activated by the UPRmt, eliminated the diet-induced shift seen in paralysis of Aβ animals. We visualized the mitochondrial morphology of Aβ animals fed two different types of bacteria, however, based on our qualitative analysis the damaging effects of Aβ on mitochondrial morphology were not altered by the type of bacteria that the Aβ animals consumed. We then measured differential gene expression in Aβ animals fed different diets through RNA-sequencing. Multiple genes involved in known protein degradation and metabolic pathways were significantly up- or down-regulated based on the diet consumed, however, UPRmt-induced genes have not been identified through this approach. Thus, we conclude that diet plays a significant role in regulation of Aβ toxicity. While activation of the UPRmt can protect against this toxicity, our discovery of additional differentially expressed genes in Aβ-expressing animals fed different diets suggests that diet likely acts through multiple pathways.